Second Course Of Radiotherapy Research Articles

Abstract PO2-22-03: Reirradiation for locally recurrent breast cancer: a long-term single centre experience

Abstract Background: About 10–15% of patients with breast cancer will eventually develop an ipsilateral breast recurrence. The management of cancer relapse in previously irradiated tissues is a challenging therapeutic issue, and data on breast re-irradiation are currently lacking. Hence, the aim of this work was to report our experience with breast re-irradiation for non-metastatic recurrent breast cancer. Material and Methods: All patients who underwent a breast or chest wall re-irradiation in the Institut Curie, Paris, France between 2003 and 2019 were identified. Those who underwent re-irradiation only in other volumes than the ipsilateral breast were excluded. Local recurrence-free (LRFS), overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), and metastasis-free survival (MFS) were evaluated. Physician-reported acute and late toxicities were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) 5.0. Results: Between 2003 and 2019, 21.372 patients underwent a breast irradiation in our institution. Of these, 453 received a new irradiation to the controlateral breast and/or lymph nodes, 105 to the homolateral lymph nodes without breast/chest wall re-irradiation and 28 received a second course of radiotherapy (RT) to the homolateral breast. These 28 patients were included in this study. Median follow up after re-irradiation was 45.5 months (IQR 33.5-79.75 months). The median age at the time of second breast RT was 63 years (IQR, 49-78). The median RT dose to the breast/chest wall was 60 Gy (interquartile range (IQR) 50-66 Gy) for the first irradiation and 48 Gy (IQR 30-50 Gy) for the second. The median cumulative dose was 100 Gy (IQR 92-114 Gy). The median time between the two courses of RT was 47 months (IQR 22.75-109.5 months). Eighteen (64%) patients were treated with a curative intent and 10 (36%) for palliative purposes. Ten (36%) had a macroscopic breast residue at re-irradiation. The second RT course was performed with electrons, photons and a combination of both in 13 (46%), 8 (29%) and 6 (21%) patients, respectively. At 2 years, LRFS, OS, DSS, PFS and MFS were respectively 59%, 79%, 82%, 50% and 75% in the whole cohort. 2-year-LRFS (72% vs 31%, p=0.02), OS (94% vs 50%, p< 0.01), DSS (94% vs 56%, p< 0.01) and PFS (61% vs 20%, p=0.02) differed significantly between patients treated in a curative or in a palliative intent, but not MFS (78% vs 69%, p=0.77). Among patients, 8 (29%) remained relapse-free 5 years after the second course of RT. Only one patient experienced an acute grade 3 adverse event (dermatitis), and 1 presented a late grade 3 one (skin fibrosis). One patient with major cardiovascular risk factors died of myocardial infarction 13 months after the second left breast irradiation. Conclusion: Breast or chest wall re-irradiation appears to be feasible with good disease control in patients treated with a curative intent, and acceptable toxicity rates. In addition, a significant number of patients were disease-free 5 years after the second course of RT. Prospective larger data with longer follow-up are needed to confirm these findings. Citation Format: Jérémy Baude, Rémi Dendale, Alain Fourquet, Youlia Kirova. Reirradiation for locally recurrent breast cancer: a long-term single centre experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-22-03.

Validation of the Lung-Mol Graded Prognostic Assessment (GPA) System for the Prognosis of Patients Receiving Radiotherapy for Brain Metastasis From Non-small Cell Lung Cancer.

The Lung-mol graded prognostic assessment (GPA) system predicts the prognosis of patients with brain metastases (BM) from non-small cell lung cancer(NSCLC) separately for adenocarcinoma and non-adenocarcinoma. This study aimed to validate the Lung-molGPA system using a cohort of patients in our institution who received radiotherapy for BM. Three hundred and thirty-nine patients with NSCLCwho received their first course of radiotherapy for BM were included in the analysis. Among them, 65 received their second course of radiotherapy for BM. Data on sex, age, Karnofsky performance status (KPS), extracranial metastases (ECM), number of BM, histological type, and gene mutations were collected according to the Lung-molGPA system. We examined the validity of the scores assigned to the factors included in the Lung-molGPA system, separately for adenocarcinoma and non-adenocarcinoma. In addition, we validated the Lung-molGPA system to predict survival during both the first and second courses of radiotherapy. The factors in the Lung-molGPA were significantly associated with survival, except for age in non-adenocarcinoma with marginal significance. Regarding discrimination ability, the C-indices were 0.65 and 0.69 for adenocarcinoma and non-adenocarcinoma, respectively, in the first course of radiotherapy for BM, while those in the second course were 0.62 and 0.74, respectively. Survival prediction by Lung-molGPA was almost consistent with actual survival in the first course of radiotherapy, except for the score of 0-1.0 in both histologies and 2.5-3.0 in non-adenocarcinoma. In the second course of radiotherapy, median survival could be predicted for some patients with adenocarcinoma. Our study confirms the validity of Lung-molGPA for the estimation of median survival based on patient characteristics at the time of initiation of radiotherapy for patients in the first course of radiotherapy and shows that it may be applicable to patients with adenocarcinoma in the second course of radiotherapy.

Meta analysis of the second course of radiotherapy for recurrent esophageal cancer1.

How to improve efficacy and reduce side effects in treating recurrent esophageal cancer by applying the second course of radiotherapy alone and its combination with chemotherapy has been attracting broad research interest. This review paper aims to systematically evaluate efficacy and side effects of applying the second course of anterograde radiotherapy alone and its combination with chemotherapy in treating recurrent esophageal cancer. First, the relevant research papers are retrieved from PubMed, CNKI and Wanfang databases. Next, Redman 5.3 software is used to calculate the relative risk and 95% confidence interval to evaluate the efficacy and adverse reactions of applying the single-stage radiotherapy with and without combining single/multi dose chemotherapy to treat recurrent esophageal cancer. Then, a meta data analysis is applied to examine the effectiveness and side effects of radiation alone and re-course radiotherapy plus chemotherapy in treating esophageal cancer recurrence after the first radiotherapy. Fifteen papers are retrieved, which included 956 patients. Among them, 476 patients received radiotherapy combined with single drug/multi drug chemotherapy (observation) and others received only radiotherapy (control). Data analysis results show that the incidence of radiation induced lung injury and bone marrow suppression is high in the observation group. Subgroup analysis also shows the higher effective rate or one-year overall survival rate of patients treated with the second course radiotherapy combined with single drug chemotherapy. The meta-analysis result demonstrates that combining the second course of radiotherapy with single-drug chemotherapy has advantages in treating recurrent esophageal cancer with the manageable side effects. However, due to insufficient data, it is not possible to conduct the further subgroup analysis comparing the side effects of restorative radiation with the combined chemotherapy using between a single drug and multiple drugs.

Radiation recall dermatitis induced by a second course of radiation therapy in the absence of clinically significant field overlap

Radiation recall dermatitis induced by a second course of radiation therapy in the absence of clinically significant field overlap

Tolerance and Oncological Outcomes of In-Field Reirradiation for Locally Recurrent Breast Cancer: A Long-Term Single-Center Experience.

The management of cancer relapse in previously irradiated tissues is a challenging therapeutic issue. The aim of this work was to report our experience with breast reirradiation for locoregionally recurrent breast cancer. All patients who underwent breast or chest wall in-field reirradiation at the Institut Curie, Paris, France, between 2003 and 2019, were identified. Efficacy outcomes and physician-reported toxicities were retrospectively assessed. A total of 21,372 patients underwent breast irradiation in our institution. Of these, 28 received a second course of radiotherapy to the homolateral breast/chest wall. A total of 18 (64%) patients were treated with a curative intent, and 10 (36%) were treated for palliative purposes. Only one acute and one late grade 3 adverse events were reported. One patient with major cardiovascular risk factors died of myocardial infarction 13 months after left breast reirradiation. The 2-year LRFS, OS, DSS, PFS and MFS were 59%, 79%, 82%, 46% and 75%, respectively, in the whole cohort. The 2-year LRFS (72% vs. 31%, p = 0.02), OS (94% vs. 50%, p < 0.01), DSS (94% vs. 56%, p < 0.01) and PFS (61% vs. 20%, p = 0.02) differed significantly between patients treated with curative or palliative intent but not the MFS (78% vs. 69%, p = 0.77). Among the patients, eight (29%) remained relapse-free 5 years after reirradiation. Breast/chest wall reirradiation appears to be feasible with good disease control, especially in patients treated with a curative intent, and presents acceptable toxicity rates.

P18.08.B COMPARISON OF DOSE CALCULATION PLANNING SYSTEMS FOR RECCURENT MENENGIOMA TREATED WITH FRACTIONATED RE-IRRIDATION

Abstract PURPOSE Meningioma is among the most common tumors of the central nervous system, accounting for approximately one-third of all brain tumors. Surgery is mainstay treatment and Radiotherapy (RT) provides long-term control in many patients, however recurrences following RT may occur and the safety and efficacy of a second course of RT is not well defined, technical and planning features are yet to be clarified. In this study, we compared various treatment planning systems (TPS) used in RT in a patient who had progressed meningioma after three applications of Gammaknife radiosurgery (GK-SRS). Case Presentation: 55-year-old male patient was diagnosed with grade-1 meningioma of the sphenoid wing in 2014 and subtotal excision was performed, with no further treatment. Progression was detected in 2016, and 11 Gy single fraction GK-SRS was applied in two sessions (inferior and superior parts of the tumor was irradiated in separate GK-SRS applications with 2 months apart) to the recurrent lesion in the right spheno-orbital region in a GK center. Patient was well until June 2022 when progression was detected in the right infratemporal region. Another GK-SRS application of 11 Gy was performed to the patient at the same institute.In April 2023 progression of the tumor was detected, tumor was irresectable and patient referred to our department for fractionated radiotherapy. Recurrent tumor was originating from right sfenoid wing and extending to right infratemporal fossa. We obtained the radiation dose distributions from the previous GK-SRS plans. Due to dose limits on the right optic nerve due to previous radiation dose disturbution , the conventional fractionated radiotherapy was planned . The PTV dose was planned to be 45 Gy/25 fx. Eclipse and Brainlab systems were compared for treatment planning. Right optic nerve dose of EQD2 was already above the limits, thus conventional fractionation (45 Gyin 25 fractions) was prescribed. Two separate plans were generated using Varian-Eclipse and Brainlab-Elements TPS, and the dose distribution of those plans were compared. Plan optimization was performed in both planning systems to provide PTV D%95. While the PTV Dmax was 57.24 Gy in BrainLAB, it was 48.7 Gy in Eclipse. Dmax doses for Brainlab and Eclipse were: right optic nerve 10.11 Gy vs. 26.9 Gy, chiasm 6.68 Gy vs. 20.5 Gy respectively. In Eclipse plan optimization, the collimator and table angles were optimized manually, while in Brainlab planning system, they were automatically handled, therefore normal tissues can be better preserved with increase of hot spots inside the PTV. This situation is observed clearly in this case. CONCLUSION Using different table and collimator angles in plan optimization can yield better results in providing normal tissue dose tolerance, especially in the irradiation of central nervous system.

Outcomes of Isocitrate Dehydrogenase Wild Type Glioblastoma after Re-irradiation.

Glioblastomas (GBM) are the most common malignant primary brain tumors in adults and have a dismal prognosis. Patients frequently suffer from local tumor recurrences, with limited therapeutic options. Re-irradiation represents a possible intervention, but given the recent 5th edition of the World Health Organization classification of central nervous system tumors, studies in isocitrate dehydrogenase wild type (IDH-wt) cohorts undergoing a second course of radiotherapy remain limited. Herein, we sought to describe our institutional experience and outcomes after GBM IDH-wt re-irradiation. GBM patients with confirmed IDH-wt status undergoing re-irradiation were included in this single-center, retrospective analysis. A total of 88 patients were analyzed. The median clinical and radiographic follow-up periods were 4.6months and 4.4months, respectively. Most patients had a Karnofsky performance status of at least 80% (n=57). The median biologically effective dose and 2Gy equivalent dose (EQD2) for re-irradiations, assuming an α/β ratio of 10Gy for GBM, were 51.4 and 42.8Gy, respectively. In total, 71 deaths were recorded. The median overall survival (OS) was 8.0months. Multivariable Cox regression of OS revealed a positive influence of gross total resection vs. biopsy or no resection (hazard ratio: 0.43, p=0.02). The median progression-free survival (PFS) was 5.9months. The multivariable Cox regression for PFS did not detect any significant factors. No clear evidence of radiation necrosis was recorded during the available follow-up. However, only a minority (n=4) of patients underwent surgery after re-irradiation, none showing histopathological proof of radiation necrosis. The prognosis for recurrent IDH-wt GBM after re-irradiation is poor. Patients who are amenable and able to undergo re-resection may have a favorable OS. A second course of radiotherapy with a moderate cumulative EQD2 and small- to medium-sized planning target volumes appeared safe regarding the occurrence of radiation necrosis.

Reirradiation of head and neck squamous cell carcinomas: a pragmatic approach, part II: radiation technique and fractionations.

Reirradiation (reRT) of local recurrent/second primary tumors of the head and neck represents a potential curative treatment for patients not candidate to a salvage surgery. Aim of the present study is to summarize literature data on modern radiation techniques and fractionations used in this setting of patients. A narrative review of the literature was conducted on three topics: (1) target volume delineation (2) reRT dose and techniques and (3) ongoing studies. Patients treated with postoperative reRT and palliative intent were not considered for the current analysis. Recommendations on the target volume contouring have been reported. 3D-Conformal Radiotherapy, Intensity Modulated Radiotherapy, Stereotactic body Radiotherapy Intraoperative Radiotherapy, Brachytherapy and Charged Particles have been analyzed in terms of indication and fractionation in the field of reRT. Ongoing studies on the topic have been reported for IMRT and Charged Particles. Moreover, according to literature data a stepwise approach has been proposed aiming to provide a useful tool to select patients candidate to a curative reRT in daily clinical practice. Two clinical cases were also provided for its application. Different radiation techniques and fractionations can be used for a second course of radiotherapy in patients with recurrent/second primary tumor of head and neck region. Tumor characteristics as well as radiobiological considerations should be take into account to define the best reRT approach.

Efficacy of a Second Course of Radiation for Patients With Metachronous Hepatocellular Carcinoma

Liver-directed radiation therapy is an effective treatment for hepatocellular carcinoma (HCC), but metachronous lesions develop outside the irradiated field in >50% of patients. We hypothesized that irradiation of these new lesions would produce an outcome like that of patients receiving a first course (C1) of treatment. We included patients with HCC who received a second course (C2) of radiation therapy >1 month after C1. Toxicity was defined as Child-Pugh score increase ≥2 within 6 months posttreatment (binary model) and as the change in albumin-bilirubin during the year after treatment (longitudinal model). Overall survival (OS) and local failure (LF) were captured at the patient and lesion level, respectively; both were summarized with Kaplan-Meier estimates. Predictors of toxicity and OS were assessed using generalized linear mixed and Cox regression models, respectively. Of 340 patients with HCC, 47 underwent irradiation for metachronous HCC, receiving similar prescription dose in C1/C2. Median follow-up was 17 months after C1 and 15 months after C2. Twenty-two percent of patients experienced toxicity after C1, and 25% experienced toxicity after C2. Worse baseline albumin-bilirubin predicted toxicity in both binary (odds ratio, 2.40; 95% CI, 1.46-3.94; P=.0005) and longitudinal models (P < .005). Two-year LF rate was 11.2% after C1 and 8.3% after C2; tumor dose (hazard ratio [HR], 0.982; 95% CI, 0.969-0.995; P=.007) and tumor size (HR, 1.135; 95% CI, 1.068-1.206; P < .005) predicted LF. Two-year OS was 46.0% after C1 and 42.6% after C2; tumor dose (HR, 0.986; 95% CI, 0.979-0.992; P < .005) and tumor size (HR, 1.049; 95% CI, 1.010-1.088; P=.0124) predicted OS. Reirradiation was not associated with toxicity (P > .7), LF (P=.79), or OS (P=.39). In this largest series in the Western hemisphere, we demonstrate that irradiation for metachronous HCC offers low rates of LF with acceptable toxicity and OS like that of patients receiving a C1. These findings support judicious selection of patients for reirradiation in metachronous HCC.

Abstract 1093: Measuring and inhibiting purine metabolism in patients with glioblastoma

Abstract Introduction: We have previously found that purine metabolism is an important metabolic mediator of treatment resistance in glioblastoma (GBM). Mycophenolate mofetil (MMF), an inhibitor of purine synthesis, synergizes with radiation and temozolomide in mouse models of GBM. No measurements of purine synthesis have been performed in human cancer patients, nor has the purine inhibitor MMF been used clinically for patients with GBM. Methods: We infused clinical-grade 13C6 glucose into patients undergoing craniotomy for presumed GBM and used mass spectrometry to measure carbon incorporation into purines in cortex and disparate tumor regions. We are conducting a phase 0/1 trial (NCT04477200) to determine the safety and potential efficacy of the purine inhibitor MMF in patients with GBM. In the phase 0 arm, patients with recurrent GBM needing tumor re-resection receive MMF for one week prior to surgery and tumor and brain tissue is analyzed by mass spectrometry to determine drug concentrations and target engagement. In the phase 1 portions, patients (age &amp;gt;18, KPS ≥ 60) with recurrent GBM are treated with MMF and a second course of radiation while patients with newly diagnosed GBM are treated with radiation (RT), temozolomide (TMZ) and MMF followed by cyclic MMF and TMZ. A TITE-CRM algorithm is employed to dose-escalate MMF (range 500-2000 mg BID) and determine its maximum tolerated dose in combination with RT and/or TMZ. Results: Stable isotope tracing has been performed on 8 patients with suspected GBM. Purine synthesis was increased in tumor tissue compared to normal cortex in all patients, with most patients having 10-30-fold increased purine labeling in tumor. We have enrolled 8 patients on our phase 0 peri-surgical study and all had active concentrations of mycophenolic acid (the active metabolite of MMF) in enhancing and non-enhancing GBM tissue. We have enrolled 28 evaluable phase 1 patients (13 recurrent, 15 new). No dose-limiting toxicities have been observed with MMF (1000-2000 mg BID) in combination with re-irradiation or cyclic TMZ. In concurrent chemoradiation with MMF, we have observed two dose limiting grade 3 toxicities at 2000 mg, both improved with treatment break. Other main toxicities are mild nausea and fatigue. Interim median overall survival in recurrent phase 1 patients is 15.6 months, which compares favorably with typical survival time of 8-10 months in this population. In the newly diagnosed cohort, median survival is not yet reached, but 14 of 15 patients are alive and without progressive tumor. Conclusions: Glucose-derived purine synthesis is elevated in human GBM compared to cortex, which could provide a favorable therapeutic index for purine synthesis inhibition. The purine synthesis inhibitor MMF achieves active concentrations in human GBM, is reasonably well tolerated in combination with standard GBM treatments, and is associated with promising preliminary clinical outcomes. Citation Format: Yoshie Umemura, Andrew J. Scott, Wajd Al-Holou, Anjali Mittal, Weihua Zhou, Kari Wilder-Romans, Jie Xu, Nathan Qi, Maureen Kachman, Michelle Kim, Larry Junck, Denise Leung, Nathan Clarke, Jason Heth, Bo Wen, Amit Pai, Vijay Tarnal, Deepak Nagrath, Theodore Lawrence, Costas A. Lyssiotis, Daniel R. Wahl. Measuring and inhibiting purine metabolism in patients with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1093.

Reirradiation of metastases of the central nervous system: part 2-metastatic epidural spinal cord compression.

An increasing number of patients irradiated for metastatic epidural spinal cord compression (MESCC) experience an in-field recurrence and require a second course of radiotherapy. Reirradiation can be performed with conventional radiotherapy or highly-conformal techniques such as intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and stereotactic body radiation therapy (SBRT). When using conventional radiotherapy, a cumulative biologically effective dose (BED) ≤120 calculated with an α/β value of 2 Gy (Gy2) was not associated with radiation myelopathy in a retrospective study of 124 patients and is considered safe. In that study, conventional reirradiation led to improvements of motor deficits in 36% of patients and stopped further symptomatic progression in another 50% (overall response 86%). In four other studies, overall response rates were 82-89%. In addition to the cumulative BED or equivalent dose in 2 Gy fractions (EQD2), the interval between both radiotherapy courses <6 months and a BED per course ≥102 Gy2 (corresponding to an EQD2 ≥51 Gy2) were identified as risk factors for radiation myelopathy. Without these risk factors, a BED >120 Gy2 may be possible. Scoring tools have been developed that can assist physicians in estimating the risk of radiation myelopathy and selecting the appropriate dose-fractionation regimen of re-treatment. Reirradiation of MESCC may also be performed with highly-conformal radiotherapy. With IMRT or VMAT, rates of pain relief and improvement of neurologic symptoms of 60-93.5% and 42-73%, respectively, were achieved. One-year local control rates ranged between 55% and 88%. Rates of myelopathy or radiculopathy and vertebral compression fractures were 0% and 0-9.3%, respectively. With SBRT, rates of pain relief were 65-86%. Two studies reported improvements in neurologic symptoms of 0% and 82%, respectively. One-year local control rates were 74-83%. Rates of myelopathy or radiculopathy and vertebral compression fractures were 0-4.5% and 4.5-13.8%, respectively. For SBRT, a cumulative maximum EQD2 to thecal sac ≤70 Gy2, a maximum EQD2 of SBRT ≤25 Gy2, a ratio ≤0.5 of thecal sac maximum EQD2 of SBRT to maximum cumulative EQD2, and an interval between both courses ≥5 months were associated with a lower risk of myelopathy. Additional prospective trials are required to better define the options of reirradiation of MESCC.

A Prospective Study of Conventionally Fractionated Dose Constraints for Reirradiation of Primary Brain Tumors in Adults

Dose constraints for reirradiation of recurrent primary brain tumors are not well-established. This study was conducted to prospectively evaluate composite dose constraints for conventionally fractionated brain reirradiation. A single-institution, prospective study of adults with previously irradiated, recurrent brain tumors was performed. For 95% of patients, electronic dosimetry records from the first course of radiation (RT1) were obtained and deformed onto the simulation computed tomography for the second course of radiation (RT2). Conventionally fractionated treatment plans for RT2 were developed that met protocol-assigned dose constraints for RT2 alone and the composite dose of RT1+RT2. Prospective composite dose constraints were based on histology, interval since RT1, and concurrent bevacizumab. Patients were followed with magnetic resonance imaging including spectroscopy and perfusion studies. Primary endpoint was the rate of symptomatic brain necrosis at 6 months after RT2. Patients were enrolled from March 2017 to May 2018; 20 were evaluable. Eighteen had glioma, 1 had atypical choroid plexus papilloma, and 1 had hemangiopericytoma. Nineteen patients were treated with volumetric modulated arc therapy, and one was treated with protons. Median RT1 dose was 57 Gy (range, 50-60 Gy). Median RT1-RT2 interval was 49 months (range, 9-141 months). Median RT2 dose was 42.4 Gy (range, 36-60 Gy). Median planning target volume was 186 cc (range, 8-468 cc). Nineteen of 20 patients (95%) were free of grade 3+ central nervous system necrosis. One patient had grade 3+ necrosis 2 months after RT2; the patient recovered fully and lived another 18 months until dying of disease progression. Median overall survival from RT2 start for all patients was 13.3 months (95% credible interval, 6.3-20.7); for patients with glioblastoma, 11.5 months (95% credible interval, 6.1-20.1). Brain reirradiation can be safely performed with conventionally fractionated regimens tailored to previous dose distributions. The prospective composite dose constraints described here are a starting point for future studies of conventionally fractionated reirradiation.

Safety of Inhomogeneous Dose Distribution IMRT for High-Grade Glioma Reirradiation: A Prospective Phase I/II Trial (GLIORAD TRIAL).

Simple SummaryGlioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor, and despite advances in imaging techniques and treatment options, the outcome remains poor and recurrence is inevitable. Salvage therapy presents a challenge, and re-irradiation can be a therapeutic option in recurrent GBM. The decision-making process for re-irradiation is a challenge for radiation oncologists due to the expected toxicity of a second course of radiotherapy and the limited radiation tolerance of normal tissue; nevertheless, it is being increasingly used, as several studies have demonstrated its feasibility. The current study aimed to investigate the safety of moderate–high-voxel-based dose escalation radiotherapy in recurrent GBM patients after conventional concurrent chemoradiation. Twelve patients were enrolled in this prospective single-center study. Retreatment consisted of re-irradiation with a total dose range of 30–50 Gy over 5 days using the IMRT (arc VMAT) technique using dose painting planning. The treatment was well tolerated. No toxicities greater than 3 were recorded; only one patient had severe G3 acute toxicity, characterized by muscle weakness and fatigue. Median overall survival (OS2) and progression-free survival (PFS2) from the time of re-irradiation were 10.4 months and 5.7 months, respectively. Our phase I study demonstrated an acceptable tolerance profile of this approach, and the future prospective phase II study will analyze the efficacy in terms of PFS and OS.Glioblastoma multiforme (GBM) is the most aggressive astrocytic primary brain tumor, and concurrent temozolomide (TMZ) and radiotherapy (RT) followed by maintenance of adjuvant TMZ is the current standard of care. Despite advances in imaging techniques and multi-modal treatment options, the median overall survival (OS) remains poor. As an alternative to surgery, re-irradiation (re-RT) can be a therapeutic option in recurrent GBM. Re-irradiation for brain tumors is increasingly used today, and several studies have demonstrated its feasibility. Besides differing techniques, the published data include a wide range of doses, emphasizing that no standard approach exists. The current study aimed to investigate the safety of moderate–high-voxel-based dose escalation in recurrent GBM. From 2016 to 2019, 12 patients met the inclusion criteria and were enrolled in this prospective single-center study. Retreatment consisted of re-irradiation with a total dose of 30 Gy (up to 50 Gy) over 5 days using the IMRT (arc VMAT) technique. A dose painting by numbers (DPBN)/dose escalation plan were performed, and a continuous relation between the voxel intensity of the functional image set and the risk of recurrence in that voxel were used to define target and dose distribution. Re-irradiation was well tolerated in all treated patients. No toxicities greater than G3 were recorded; only one patient had severe G3 acute toxicity, characterized by muscle weakness and fatigue. Median overall survival (OS2) and progression-free survival (PFS2) from the time of re-irradiation were 10.4 months and 5.7 months, respectively; 3-, 6-, and 12-month OS2 were 92%, 75%, and 42%, respectively; and 3-, 6-, and 12-month PFS2 were 83%, 42%, and 8%, respectively. Our work demonstrated a tolerable tolerance profile of this approach, and the future prospective phase II study will analyze the efficacy in terms of PFS and OS.

Intracranial Meningioma in a Dog - Treatment with Radiotherapy

Background: The most common primary brain neoplasm is meningioma. Dolichocephalic breeds are predisposed and there is no sexual predilection. Clinical signs depend on the location and size of the tumor and have a progressive course. Primary treatement includes surgery, radiotherapy or both. This study aimed to describe the treatment of a dog with suspected intracranial meningioma with definitive radiotherapy, which resulted in significant clinical improvement and prolonged survival. Case: A 9-year-old Shetland Shepherd bitch was diagnosed with a head tilt to the left side that progressed over a few weeks. She previously received corticosteroid therapy, which resulted a clinical improvement that worsened after treatment was discontinued. Computed tomography revealed an extra-axial brain mass in the caudal fossa, lateralized to the right, well-delimited, and measuring approximately 1.5 × 1.4 × 1.7 cm, suggestive of intracranial meningioma. The patient was treated with radiotherapy using Cobalt-60 equipment, with 18 daily fractions of 2.5 Gy at a total dose of 45 Gy using parallel and opposite technique fields. A new tomography performed 30 days after treatment showed a remission of 85% of the initial brain mass measuring approximately 0.9 × 1.0 × 0.5 cm, as well as complete resolution of the clinical signs initially presented. After 14 months, the patient presented with signs of lethargy and ataxia and was medicated with hydroxyurea at a dose of 50 mg/kg 3 times a week and corticosteroid therapy. However, the patient’s neurological condition deteriorated, and she was subjected to reirradiation using the same protocol used previously, which resulted in clinical improvement and a 54% reduction in tumor volume on magnetic resonance. As a late side effect, only permanent alopecia in the irradiated region was observed. The patient died of disease 330 days after the second course of radiotherapy, with a total survival time of 1087 days. Discussion: Meningiomas are extra-axial neoplasms of the central nervous system that grow inside the dura mater. The literature shows that meningiomas are more common in dolichocephalic races with a mean age of 9 years, which supports our findings. Meningiomas most commonly affect the cortical thalamus and cerebellopontine region in dogs, which are normally associated with vestibular symptoms, as seen in this case. Diencephalic damage can result in vestibular signals since the thalamus functions as a relay station for vestibular afferent stimuli that are relayed to the cerebral cortex. In addition to the vestibular syndrome, common clinical signs associated with meningiomas in dogs include seizures, behavioral changes, and walking in circles, which are frequently misinterpreted due to tumor-induced side effects, such as cerebral edema, obstructive hydrocephalus, and cerebral hernia. Advanced imaging techniques should be used to diagnose intracranial neoplasms. In this case, computed tomography was critical for diagnosis and treatment planning. Meningioma treatment may comprise palliative measures, surgery, and radiotherapy. Radiotherapy as a single treatment can improve the quality of life with a decrease in clinical signs and a median survival time of approximately 250-536 days, as reported in the literature. Hydroxyurea can be a therapeutic option in inoperable cases and for patients with clinical limitations to undergo successive anesthesia during radiotherapy. Its most serious side effect is progressive myelosuppression. It can cause temporary partial tumor remission and improvement in clinical signs. As previously stated, radiotherapy can be an effective primary treatment option for treating intracranial meningiomas in dogs, with significant improvement in neurological clinical signs and mild side effects. Keywords: dogs, central nervous system, radiotherapy, reirradiation, oncology. Título: Meningioma intracraniano em cão - tratamento com radioterapia Descritores: cães, sistema nervoso central, radioterapia, reirradiação, oncologia.

Brachial Plexus Tolerance to High-Dose Radiation in the Re-Irradiation Setting

<h3>Purpose/Objective(s)</h3> Radiotherapy (RT) is a cornerstone modality in treating head and neck cancers in the primary and salvage settings. Maximum tolerated dose to the brachial plexus and other factors contributing to brachial plexus injury in the re-irradiation setting are poorly understood. To define radiation dose and other clinical factors associated with the brachial plexus injury in patients treated with re-irradiation for recurrent head and neck cancers. <h3>Materials/Methods</h3> We analyzed 47 brachial plexus re-irradiation between 2015 and 2020. A first course of radiation for head and neck cancer, developed recurrent disease, and then underwent salvage re-irradiation. DICOM plans and contours for all patients were reviewed by two authors and via a prospective multidisciplinary chart rounds. Common terminology criteria for adverse events (CTCAE) was used to define the brachial plexus injury after the second course of radiation. We used ROC curves to evaluate the cutoff values. Kaplan-Meier and logistic regression were used to test the correlation between the variables and the outcome. <h3>Results</h3> Median prescription dose from the 1st course was 70 Gy (range: 60-70) and from the 2nd course was 66 Gy (46-70) in 2 Gy per fraction. All patients received photon volumetric modulated arc therapy; 74% received concurrent chemotherapy (CRT) during the 1st course (Cisplatin 30%, Carboplatin +/- Paclitaxel 23% and Cetuximab 21%), 74% received CRT during the 2nd course (Carboplatin/Paclitaxel 40%, Cetuximab 17%, Cisplatin 13% and Nivolumab 4%) and 53% received CRT twice. The median time interval between the two RT courses was 24 months (range, 8-221 months). The median cumulative maximum dose (Dmax) to brachial plexus was 97 Gy (range, 64-144 Gy). At a median follow-up of 9 months (range, 1-47 months), the cumulative incidence of brachial plexopathy (CIBPP) was 17% at 1 year. This consisted of two cases with pain alone, one case with numbness alone, two cases with weakness alone and one case with combination of pain and numbness. The median time to development of symptoms was 8.2 months (range, 1-15 months). Among patients with a Dmax greater than vs less than 106 Gy, the 1-year cumulative incidence of BPP was 42% vs 4% <i>P</i> = 0.005. V80 > 1cc (1-yr CIBPP 34% vs 4% <i>P</i> = 0.03) and V90 > 0.3cc (32% vs 4%, <i>P</i> = 0.046) associated with increased risk of BPP. The use of concurrent cisplatin during re-irradiation was associated with increased risk of BPP (OR 39 CI 4.263-356.81, <i>P</i> = 0.001). Other variables like gender, history of neck surgery, use of other kind of systemic therapy, use of cisplatin during the first course of RT, mean cumulative dose, V60, V70, V100 and the interval between the first and the second courses of radiation were not associated with increased risk of BPP. The 1-year OS was 78% and the 1-year PFS was 52%. <h3>Conclusion</h3> Cumulative incidence of radiation-induced BPP after re-irradiation was 17% at 1 year. Dmax > 106 Gy, higher V80/V90, and the use of concurrent cisplatin during re-irradiation, were associated with increased risk of BPP.

Updated Outcomes of Split Course Radiotherapy in Elderly or Infirm Patients With Advanced Cancers of the Head and Neck.

Head and neck cancers are often treated with extended courses of radiotherapy (RT), which may prove excessively toxic for frail patients. Split course RT (SCRT) delivers two courses of RT separated by 4-6 weeks, personalizing treatment intensity based on response. In this study, we present our updated experience using this technique. From a single institution database, we identified patients considered for SCRT. For patients undergoing a second course of RT, cumulative incidence of locoregional recurrence (LRR) and overall survival (OS) are reported. A total of 98 patients were included, of whom seventy-five percent underwent a second course of RT. The most common fractionation was 30 Gy in 10 fractions for each course, with a median cumulative dose of 60 Gy. In those undergoing a second course of RT, median OS was 9.7 months and cumulative incidence of LRR at 6, 12, and 24 months was 17.0%, 23.1%, and 29.4%, respectively. SCRT offers an attractive treatment paradigm to personalize radiation intensity based on patient tolerance, while maintaining reasonable safety and efficacy in those unfit for standard full course RT.

Craniospinal irradiation as part of re-irradiation for children with recurrent medulloblastoma

Many studies have demonstrated in the last years that once medulloblastoma has recurred, the probability of regaining tumor control is poor despite salvage therapy. Although re-irradiation has an emerging role in other relapsed brain tumors, there is a lack of strong data on re-irradiation for medulloblastoma. This is a retrospective cohort study of patients aged 18 years or under, treated at least by a second course of external beam for recurrence medulloblastoma at Garrahan Hospital between 2009 and 2020. Twenty-four patients met eligibility criteria for inclusion. All patients received upfront radiotherapy as part of the curative-intent first radiotherapy, either craniospinal irradiation (CSI) followed by posterior fossa boost in 20 patients or focal posterior fossa radiation in 4 infants. The second course of radiation consisted of CSI in 15 and focal in 9. The 3-year post first failure OS (50% vs. 0%; p = 0.0010) was significantly better for children who received re-CSI compared to children who received focal re-irradiation. Similarly, the 3-year post-re-RT PFS (31% vs. 0%; p = 0.0005) and OS (25% vs. 0%; p = 0.0003) was significantly improved for patients who received re-CSI compared to patients who received focal re-irradiation. No symptomatic intratumoral haemorrhagic events or symptomatic radionecrosis were observed. Survivors fell within mild to moderate intellectual disability range, with a median IQ at last assessment of 58 (range 43-69). Re-irradiation with CSI is a safe and effective treatment for children with relapsed medulloblastoma; improves disease control and survival compared with focal re-irradiation. However this approach carries a high neurocognitive cost.

Stereotactic radiation therapy for recurrent nasopharyngeal carcinoma

: Radiation therapy is the mainstay treatment modality for nasopharyngeal carcinoma. Recurrent disease affects about 10% of patients, and reirradiation is the most common treatment for recurrent nasopharyngeal carcinoma. Serious complications are not uncommon during the second course of radiation therapy because of the full-tolerance radiation dose applied to normal tissue. Catastrophic toxicity may be induced by treatment for recurrent nasopharyngeal tumor. Salvage surgery has a 3-year overall survival of 85.8% with a 5% incidence of late fatal toxicity. However, the surgical approach is still relatively new with limited information and experience regarding its optimal implementation. Another technique used for recurrent nasopharyngeal carcinoma is stereotactic radiation therapy (SRT), which delivers radiation to a specific target with a rapid dose fall-off to adjacent normal tissue that can reduce the risk of complications. Single-shot radiation therapy for nasopharyngeal carcinoma has a local control rate of up to 72% for 2 years, although there is a 10% chance of cranial neuropathy and temporal lobe necrosis. Conventional fractionated SRT has shown a 3-year control rate of 56% with complications of 11% nasopharyngeal necrosis and 8.3% nasal bleeding. Hypofractionation SRT with a large fraction dose has demonstrated a 5-year control rate of 78% with a 12.5% to 16% incidence of fatal complications. Local recurrent nasopharyngeal carcinoma with a limited volume should be treated with SRT. For reirradiation, the dose constraints in organs at risk (OARs) of recurrent nasopharyngeal carcinoma are critical. Despite the lack of data regarding SRT, the radiation doses of OARs in SRT may be converted to a biologically equivalent dose and summed with doses of primary radiation therapy for evaluation. Hypofractionation may have an optimal treatment response rate with acceptable complications. For recurrent nasopharyngeal carcinoma, SRT has shown certain therapeutic advantages, but conventional fractionation radiation therapy may still be the appropriate setting for reirradiation. Patients undergoing SRT should be counseled carefully before initiation of therapy, especially if the targets are close to a critical organ that may cause serious side effects. The treatment decision of recurrent nasopharyngeal carcinoma should be based on the patient’s overall condition and disease status.

Single institution experience in re-irradiation of biopsy-proven diffuse intrinsic pontine gliomas.

Diffuse intrinsic pontine glioma (DIPG) is the leading cause of death from CNS tumors in children. Multiple clinical trials have failed to show any benefit from systemic therapy in DIPG, and radiation therapy (RT) alone remains the standard of care. Re-irradiation (rRT) for symptomatic relief is an option at disease progression. However, published data on treatment details and outcomes are limited. The objective of this study was to review and report our institutional experience with re-irradiation of patients with biopsy-proven DIPG. We identified a cohort of pediatric patients with biopsy-proven DIPG with clinical disease progression after initial radiotherapy who received a second course of radiotherapy at our institution. We reviewed patient and treatment characteristics and outcomes. Between January 2014 and July 2018, we identified five patients with progressive DIPG who received re-irradiation. Re-irradiation was well tolerated with no serious adverse events reported and all patients experiencing stable to improved neurologic function during treatment. Median survival from completion of re-irradiation was 116 days (range 62 to 159 days). Median overall survival from time of diagnosis was 16.3 months (range 13.0 to 18.0 months), which is longer than the historical average of less than 12 months. In patients with available postmortem neuropathology, common findings were Wallerian degeneration and necrosis. In our experience, re-irradiation is safe and feasible for patients with DIPG with symptomatic disease progression following initial radiotherapy treatment.

Radiation Recall Pneumonitis After Treatment With Checkpoint Blockade Immunotherapy: A Case Series and Review of Literature.

BackgroundRadiation recall pneumonitis (RRP) is a poorly understood clinical syndrome in which patients develop radiation pneumonitis triggered by a systemic agent, often years after the completion of radiation therapy. Immune checkpoint blockade agents have only recently been posited as a trigger for RRP. Here, we present three cases of immunotherapy-induced RRP.Case PresentationOur first patient was diagnosed with primary lung adenocarcinoma, and 4.5 years after completing radiation therapy developed symptomatic RRP immediately following a second dose of nivolumab-containing immunotherapy regimen. Our second patient was diagnosed with primary bladder cancer metastatic to the mediastinum, which was treated twice with radiation therapy. He developed RRP in the days following his second course of ipilimumab-pembrolizumab which was months after his second course of radiation that he received. Our final patient was diagnosed with metastatic small cell lung cancer and received local consolidative radiation therapy in addition to whole-brain radiation. He developed RRP on the 11th day after concluding his 4th cycle of nivolumab-ipilimumab, approximately 7 months after having had completed chest radiation therapy.ConclusionsImmunotherapy-induced RRP is a rare diagnosis which can present more focally than traditional immunotherapy pneumonitis and which must be clinically differentiated from other local processes such as pneumonia. Further research should explore the mechanisms underlying these radiation recall reactions as many patients receive radiation and immunotherapy during the course of their cancer treatment.